Download Mechanism for Cell-Mediated Immunity Macrophage Activation as

Macrophage Activation as an Effector
Mechanism for Cell-Mediated Immunity
Vincent C. Tam and Alan Aderem
This information is current as
of June 17, 2017.
References
Subscription
Permissions
Email Alerts
http://www.jimmunol.org/content/suppl/2014/09/25/193.7.3183.DC1
This article cites 11 articles, 9 of which you can access for free at:
http://www.jimmunol.org/content/193/7/3183.full#ref-list-1
Information about subscribing to The Journal of Immunology is online at:
http://jimmunol.org/subscription
Submit copyright permission requests at:
http://www.aai.org/About/Publications/JI/copyright.html
Receive free email-alerts when new articles cite this article. Sign up at:
http://jimmunol.org/alerts
The Journal of Immunology is published twice each month by
The American Association of Immunologists, Inc.,
1451 Rockville Pike, Suite 650, Rockville, MD 20852
Copyright © 2014 by The American Association of
Immunologists, Inc. All rights reserved.
Print ISSN: 0022-1767 Online ISSN: 1550-6606.
Downloaded from http://www.jimmunol.org/ by guest on June 17, 2017
Supplementary
Material
J Immunol 2014; 193:3183-3184; ;
doi: 10.4049/jimmunol.1402046
http://www.jimmunol.org/content/193/7/3183
The
Pillars of Immunology
Journal of
Immunology
Macrophage Activation as an Effector Mechanism for
Cell-Mediated Immunity
Vincent C. Tam and Alan Aderem
M
Seattle Biomedical Research Institute, Seattle, WA 98109
Address correspondence and reprint requests to Dr. Alan Aderem, Seattle Biomedical
Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109.
E-mail address: [email protected]
Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402046
in recipient animals. Mackaness also observed that the emergence of delayed-type hypersensitivity, now known as a surrogate for assessing cell-mediated immunity, coincided with the
antibacterial response. Detailed histological studies of the spleen
and liver identified mononuclear cells as the dominant population during secondary challenge. Macrophages isolated
from previously infected animals were distinct morphologically and phenotypically from macrophages isolated from naive
animals. These ex vivo macrophages from immunized animals
were also resistant to Listeria infection in vitro. The data led
him to conclude that macrophages from mice previously
infected with intracellular pathogens were resistant to secondary challenge. In subsequent work also highlighted here,
using L. monocytogenes, Brucella abortus, and Mycobacterium
tuberculosis, Mackaness demonstrated that these activated
macrophages have nonspecific resistance to unrelated pathogens, but only when cellular immunity has been established
in vivo (3). This resistance was due to enhanced nonspecific
bactericidal activities within the macrophage. Finally, he demonstrated that lymphocytes transferred from immunized
animals altered the bactericidal activity of the recipient macrophages (8, 9). Thus, the interdependence of the innate and
adaptive immune responses in successfully protecting the
host against intracellular pathogens was revealed. Mackaness’
seminal work set the stage for the molecular characterization
of macrophage activation, such as the 1983 publications by
two groups, first-authored by Carl Nathan and Robert
Schreiber, demonstrating that T cell–secreted IFN-g was the
factor that stimulated macrophages to increase their bactericidal
activity during cellular immunity (10, 11). Mackaness’ work
clearly demonstrated the involvement of macrophages in the
complex interactions between cells that play key roles in innate
and adaptive immunity, and it laid the foundation for current
research focused on dissecting the mechanisms that drive this
crosstalk.
Disclosures
The authors have no financial conflicts of interest.
References
1. Steinman, R. M., and Z. A. Cohn. 1973. Identification of a novel cell type in
peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J. Exp. Med. 137: 1142–1162.
2. Mackaness, G. B. 1962. Cellular resistance to infection. J. Exp. Med. 116: 381–
406.
3. Mackaness, G. B. 1964. The immunological basis of acquired cellular resistance. J.
Exp. Med. 120: 105–120.
4. Raffel, S. 1949. Types of acquired immunity against infectious disease. Annu. Rev.
Microbiol. 3: 221–264.
Downloaded from http://www.jimmunol.org/ by guest on June 17, 2017
yeloid cells function as major bridges between
the innate and adaptive immune systems. First,
dendritic cells orchestrate an appropriate adaptive immune response through Ag presentation, a landmark
finding that garnered a Nobel Prize for Ralph Steinman (1).
Less well known are the findings of George Mackaness from
the John Curtin School of Medical Research in Australia, who
demonstrated a second intersection between the innate and
adaptive immune responses: that macrophages can serve as
effector cells for acquired cell-mediated immunity. In 1962,
his article titled “Cellular Resistance to Infection” was published in The Journal of Experimental Medicine (2), highlighted here along with a second seminal article by Mackaness
from 1964 (3) as a Pillar of Immunology. At the time, Abdependent immune responses were well appreciated, but cellular immunity was not generally accepted. However, there
were a number of lines of evidence that pointed to a major
role for cellular immunity. For example, the humoral response
alone did not correlate with protection in all infections, especially ones caused by intracellular pathogens (4).
Mackaness used Listeria monocytogenes, a facultative, intracellular pathogen, to investigate cellular resistance (2). His
decision to use this pathogen was based on previous observations suggesting that the clearance of L. monocytogenes was
not dependent on humoral immunity (5, 6). Because the parental strain of L. monocytogenes was unable to persist in mouse
macrophages, Mackaness used serial passaging, a technique
described in the original discovery of L. monocytogenes (7), to
enhance its virulence. Interestingly, the bacterium increased in
virulence regardless of whether it had been passaged in vivo or
in cultured macrophages. This observation legitimized the in
vitro infection model that was used in parallel with the mouse
model. With L. monocytogenes as the pathogen and outbred
mice as the host, Mackaness demonstrated acquired cellular
immunity by primary infection and secondary challenge.
Whereas naive animals were susceptible to Listeria infection,
previously infected animals could withstand a secondary infection of 10 LD50 (2). This acquired resistance persisted for
at least 13 wk after primary infection. The role of Abs in
acquired resistance to Listeria was ruled out when serum
from immunized animals failed to reduce bacterial growth
3184
5. Osebold, J. W., and M. T. Sawyer. 1957. Immunization studies on listeriosis in
mice. J. Immunol. 78: 262–268.
6. Julianelle, L. A. 1941. Biological and immunological studies of Listerella. J. Bacteriol. 42: 367–383.
7. Murray, E. G. D., R. A. Webb, and M. B. R. Swan. 1926. A disease of rabbits
characterised by a large mononuclear leucocytosis, caused by a hitherto undescribed
bacillus Bacterium monocytogenes (n.sp.). J. Pathol. 29: 407–439.
8. Mackaness, G. B. 1969. The influence of immunologically committed lymphoid
cells on macrophage activity in vivo. J. Exp. Med. 129: 973–992.
PILLARS OF IMMUNOLOGY
9. Mackaness, G. B., and W. C. Hill. 1969. The effect of anti-lymphocyte globulin on
cell-mediated reistance to infection. J. Exp. Med. 129: 993–1012.
10. Nathan, C. F., H. W. Murray, M. E. Wiebe, and B. Y. Rubin. 1983. Identification
of interferon-gamma as the lymphokine that activates human macrophage oxidative
metabolism and antimicrobial activity. J. Exp. Med. 158: 670–689.
11. Schreiber, R. D., J. L. Pace, S. W. Russell, A. Altman, and D. H. Katz. 1983.
Macrophage-activating factor produced by a T cell hybridoma: physiochemical
and biosynthetic resemblance to gamma-interferon. J. Immunol. 131: 826–
832.
Downloaded from http://www.jimmunol.org/ by guest on June 17, 2017